The cryo-electron microscopy structure of huntingtin

Nature
Qiang GuoStefan Kochanek

Abstract

Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington's disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely...Continue Reading

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Datasets Mentioned

BETA
EMD-3984

Methods Mentioned

BETA
size-exclusion chromatography
differential scanning fluorimetry
PCR
size exclusion chromatography
transfection
acetylation

Software Mentioned

COOT
PSIPRED
Proteome Discoverer
CTFFIND4
real
MotionCor2
Perseus
RELION
Phenix
SPHIRE

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